This project is a continuation of work already in progress directed toward the elucidation of the joint contracture process in biochemical, bioengineering, and morphologic terms, and toward the development of therapeutic programs which will minimize contracture formation. Major changes in the composition of fibrous connective tissue have been demonstrated in experimental joint contractures as a result of immobilization. These changes were uniformly observed in ligaments, tendons, fascia and capsular tissue of the knee joint. Significant correlations between measures of strength of contracture and reduction in content of total hexosamine, water, and hyaluronic acid in the connective tissue matrix were shown. A working hypothesis was constructed to explain these observations: The loss of water and glycosaminoglycans in the periarticular connective tissue of immobilized joints contributes to changes in the physical characteristics of the affected joints. Presumably, this role is a permissive one, allowing closer proximity of critical intercept points in the immobilized fibrous connective tissue matrix which allows cross-links through one of two mechanisms: a) random disposition of newly synthesized collagen or b) covalent cross-links between pre-existing fibers. Significant increase of DHLNL, HLNL and HHMD in immobilized connective tissue has been demonstrated. Under this formulation, the fixed posture at the intercept points translates into restriction of motion in the joint composite. Collagen turnover studies are planned using the 3H proline prelabeling technique of Klein to determine mass differences of new and old collagen in immobilized joints. This information is required to interpret the cross-link changes, as increases in reducible cross-links may simply reflect increased collagen synthesis. Pilot projects are planned to search for myofibroblasts in joint controacture tissue as well as ratios of Type I to Type III collagen. Therapeutic agents which hold promise in the prevention of contracture include penicillamine, estradiol, hydrocortisone, indiomethacin (an inhibitor of prostoglandin) and CANa2 EDTA. Pilot screening program for evaluation of potential drug and hormone applicants for this purpose is also proposed.